Symptoms of phaeochromocytoma

The wide spectrum of symptoms of this tumour are explained by the adrenaline and noradrenaline released into the circulation, which mimic the effects of sympathetic nervous system stimulation. In up to 90% of cases there is sustained or episodic hypertension (high blood pressure), often difficult to control medically. True episodic hypertension occurs in less than 50% of cases.

Although rare tumours, approximately 0.1-0.5% of patients with hypertension will have a phaeochromocytoma, and they are found at autopsy in 0.1%, especially in patients who die suddenly of myocardial infarction or stroke.

The classical triad of symptoms of a phaeochromocytoma are headache, palpitations and extreme hypertension, usually occurring episodically.

Typically patients with phaeochromocytoma will present in one of four ways:

  • symptoms (headache, hypertension, sweating, etc.)
  • incidental (e.g. an abdominal CT scan)
  • deliberate screening (in genetic family)
  • sudden death

About half of all patients presenting with an unexplained spontaneous adrenal haemorrhage will have a phaeochromocytoma. In these cases cautious and considered investigation and preparation should be undertaken prior to any consideration of surgery.

Typical symptoms, with their frequency shown in brackets, include the following:

  • hypertension (80-90%)
  • headache (60-90%)
  • palpitations (50-70%)
  • sweating (55-75%)
  • pallor / pale appearance (40-45%)
  • nausea and/or vomiting (20-40%)
  • flushing (10-20%)
  • weight loss (20-40%)
  • tiredness (25-40%)
  • anxiety or panic attacks / feeling of ‘impending doom’ (20-40%)

Phaeochromocytoma crises

Fig.1: Statue perhaps showing the headache a paraganglioma patient feels when passing urinePatients present with symptoms which occur in either:

  • spells (paroxysmal episodes)
  • sustained
  • crises

Many patients experience paroxysmal spells or crises characterised by the classic triad of headaches, palpitations and extreme hypertension (high blood pressure). The paroxysms may last for a few minutes to several hours. A phaeochromocytoma crisis is a medical emergency, and is one of the most common causes of sudden death. Half of the patients have normal blood pressure between episodes.

The crisis is caused by an abrupt release of catecholamines from the phaeochromocytoma, leading to a massive activation of the sympathetic nervous system, hence the feeling of 'impending doom'. Sympathetic nervous system activation is a normal part of life, producing the symptoms of anxiety,  palpitations, sweating, etc. experienced as part of the normal 'fight or flight' response.

The far more pronounced attacks experienced by phaeochromocytoma patients can be triggered in a variety of ways:

  • physical triggers
    Nearly anything that puts pressure on the tumour, such as certain twisting movements, increased abdominal pressure of defaecation, urination, child birth, exercise and trauma. Phaeochromocytomas in the bladder (paragangliomas) can present as episodic hypertension, triggered when passing urine (Fig. 1).
  • chemical triggers
    Alcohol, tobacco
  • invasive medical procedures
    Surgical and anaesthetic procedures like diagnostic needle biopsy, angiography and minor surgery can all induce a paroxysm

Diagnosis of Phaeochromocytoma

Diagnosis of a phaeochromocytoma requires a high index of suspicion as it can mimic many other conditions. Tests need to be highly sensitive to the disease in order to pinpoint a phaeochromocytoma or paraganglioma as the cause of hypertension. In addition, test results can be affected by the concurrent administration of certain drugs, such as a-blockers , b-blockers, calcium channel blockers and phenothiazines.

The main steps in the diagnosis are:

  • confirmation of biochemical diagnosis
  • any tumours must be localised
  • genetic testing

The aim is to establish the biochemical diagnosis and locate the tumour prior to its removal, usually by laparoscopic or posterior retroperitoneoscopic adrenalectomy.

1. Confirmation of the biochemical diagnosis

Once a phaeochromocytoma is suspected, with identification of the classic symptoms and signs, patients need to be screened for the tumour. This also applies to those patients who are asymptomatic and have an incidental finding of an adrenal mass on CT scanning.

Screening is achieved by either blood testing, urine testing or both.

Plasma free metanephrines is the most common screening test, and is now freely available. It can be less specific with potential factitious catecholamine elevation due to anxiety, with a false-positive rate of 10-15%, so repeating the test several times will help. During a paroxysmal crisis however, this type of test is useful to detect the abnormally high levels of catecholamine. In hypertensive patients a normal metanephrine result suggests a cause other than a catecholamine-secreting tumour.

Metanephrine levels can be affected by some psychiatric drugs and beta blockers, so caution is advised in the interpretation of results in these patients.

If there is only an isolated rise in normetadrenaline, or a very mild rise just above the normal range, this is likely to be a false positive and the test should be repeated. Elevation of both the normetadrenaline and metadrenaline is likely to be a real indication of a phaeochromocytoma.

24-hour urinary metanephrines or urinary catecholamines are highly specific tests,  although it is possible to use nocturnal collection, one hour samples or even spot collection. In a normal person the 24 hour urinary excretion of free noradrenaline is <675 nmol/day and adrenaline is <275nmol/day. Care needs to be taken when patients are under extreme stress, or are taking tricyclic antidepressants, alpha methyldopa or labetalol as these can interfere with results.

Suppression tests rarely can also be used to confirm the diagnosis when anxiety may cause the readings of catecholamines to be ambiguous. Using pentolinium (2.5mg i.v. at t=0 and then sample plasma catecholamines at 0 and 1 hour) can help distinguish between tumour-produced catecholamines and those produced due to stress as it does not suppress catecholamines from tumours. Clonidine (300µg orally at t=0, plasma catecholamines sampled at 0, 120 and 180 minutes) may also be used for these purposes.

2. Localising the tumour

Imaging is a vital tool in localising the tumour. As 90% of the chromaffin tumours occur in the abdomen and pelvis, CT and MRI scanning will usually detect phaeochromocytomas in the adrenals, but also paragangliomas elsewhere in the abdomen, and possible metastases in the case of malignancy.

Most phaeochromocytomas are >3cm in size at presentation, with a density > 10HU.

CT & MRI scan

Fig.2: CT scans of large phaeochromocytoma (arrow, left & centre) and paraganglioma (arrow, right)CT scanning has a 93% sensitivity, and is the imaging modality of choice in detecting tumours >1.0 cm in diameter (Fig. 2). Care must be taken not to give intravenous contrast however, as this can trigger catecholamine release and a hypertensive crisis.

MRI can detect the tumours with almost 100% sensitivity, due to better tissue characterisation. If a CT/MRI scan shows no tumour, yet the biochemical tests suggest the presence of one, then a whole body scan must be done to locate the tumour.

MIBG  & 68Gallium Dotatate Scan

Fig.3: MIBG scan showing clear signal of a right adrenal phaeochromocytomaMIBG scanning has largely been superseded now by 68Gallium dotatate scanning, which has a detection rate of 80-100%. It will also locate additional incidental tumours like thyroid nodules and paarathyroid adenomas, etc.

Confirmation of an adrenal phaeochromocytoma or paraganglioma can also be obtained with meta-iodobenzylguanidine (123I-MIBG) scanning (Fig. 3). This compound binds to chromaffin and can help visualise the lesion, plus any metastases in the case of suspected malignancy, with a sensitivity of 85-90% and a specificity of over 95%.

In practice neither is a vital test if the tumour has been well localised by CT or MRI scans.

PET scan

Fig. 4: FDG-PET (left) and MIBG (right) of a patient with metastatic malignant phaechromocytoma (arrowed). The lower opacity in each image is the bladder.A newer technique with some promise in confirming phaeochromocytomas or paragangliomas, and locating metastases in the case of malignancy, is scanning with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) PET (positron emission tomography) (Fig. 4).

Most phaeochromocytomas accumulate FDG, with uptake found in a greater percentage of malignant than benign phaeochromocytomas. FDG PET is especially useful in defining the distribution of those phaeochromocytomas that fail to concentrate MIBG.

3. Genetic testing

As potentially up to 30% of phaeochromocytomas and paragangliomas have a hereditary basis, there is ample justification for all patients being referred for genetic screening, particularly if there is a strong family history or the presence of additional symptoms and signs characteristic of other tumours found in the associated syndromes. Younger patients (under the age of 50 years), and patients with extra-adrenal, bilateral or multiple phaeochromocytomas should always be referred for testing.

The reason for testing is that there is a clear benefit for the patient in finding other tumours that occur in the various tumour syndromes and treating them early. There is also a clear benefit for their family members, who can be screened and potentially diagnosed and treated earlier if affected.

Screening for RET, VHL, SDHB and SDHD mutations should be undertaken, using a genetic screening service or family cancer clinic.

 

Next page: Treatment of Phaeochromocytoma